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Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae
Rother C, Uhlmann RE, Müller SA, Schelle J, Skodras A, Obermüller U, Häsler LM, Lambert M et al.. Nature communications, 2022-11-28
Topic: Brain proteins, microglia and lab models
Brain Aβ deposition is a key early event in the pathogenesis of Alzheimer´s disease (AD), but the long presymptomatic phase and poor correlation between Aβ deposition and clinical symptoms remain puzzling. To elucidate the dependency of downstream pathologies on Aβ, we analyzed the trajectories of cerebral Aβ accumulation, Aβ seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in Aβ-precursor protein transgenic mice. We find that Aβ deposition increases linearly until it reaches an apparent plateau at a late age, while Aβ seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of Aβ generation in amyloid-laden mice reduced Aβ deposition and associated glial changes, but failed to reduce Aβ seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of Aβ generation was started at pre-amyloid stages, CSF NfL did not increase despite some Aβ deposition, microglial activation, and robust brain Aβ seeding activity. A dissociation of Aβ load and CSF NfL trajectories was also found in familial AD, consistent with the view that Aβ aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when Aβ seeding activity is saturated and before Aβ deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Rother, C., Uhlmann, R. E., Müller, S. A., Schelle, J., Skodras, A., Obermüller, U., et al. (2022). Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae. Nature communications. https://doi.org/10.1038/s41467-022-34538-5
Vancouver
Rother C, Uhlmann RE, Müller SA, Schelle J, Skodras A, Obermüller U, et al. Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae. Nature communications. 2022. doi:10.1038/s41467-022-34538-5. PMID: 36443293.
BibTeX
@article{rother2022-36443293,
author = {Rother, C. and Uhlmann, R. E. and Müller, S. A. and Schelle, J. and Skodras, A. and Obermüller, U. and Häsler, L. M. and Lambert, M. and others},
title = {{Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae}},
journal = {Nature communications},
year = {2022},
doi = {10.1038/s41467-022-34538-5},
pmid = {36443293},
url = {https://doi.org/10.1038/s41467-022-34538-5}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- We find that Aβ deposition increases linearly until it reaches an apparent plateau at a late age, while Aβ seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL.
- Short-term inhibition of Aβ generation in amyloid-laden mice reduced Aβ deposition and associated glial changes, but failed to reduce Aβ seeding activity, and CSF NfL continued to increase although at a slower pace.
- When short-term or long-term inhibition of Aβ generation was started at pre-amyloid stages, CSF NfL did not increase despite some Aβ deposition, microglial activation, and robust brain Aβ seeding activity.
- A dissociation of Aβ load and CSF NfL trajectories was also found in familial AD, consistent with the view that Aβ aggregation is not kinetically coupled to neurotoxicity.
- Rather, neurodegeneration starts when Aβ seeding activity is saturated and before Aβ deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease.
Why it matters
In mice, blocking Aβ production reduced Aβ deposits but did not stop the rise of a neurodegeneration marker, suggesting Aβ buildup and nerve damage are not tightly linked. This is animal research, so it does not yet show whether the same is true in people or whether any treatment approach would work.
New to this subject? Start with our plain-English guide: Blood tests & biomarkers →
Study details
- Evidence strengthLow
How this study scored 50/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature communications) |
| Journal's citation record | 4 / 4 | Nature Communications: journal h-index 747 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 28 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 4.7 citations a year over 6 year(s) since 2022 |
| Impact for its field and year | 3 / 6 | Cited 3.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 2 / 4 | Cited 23 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Mathias Jucker: h-index 94 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Massachusetts General Hospital: institution h-index 2,057 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 12 institution(s) in 4 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 36443293) |
| Free to read | 2 / 2 | Free to read |
| Total | 50 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41467-022-34538-5
- PubMed: 36443293
- Original source →
- Free full text: Nature Communications →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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